There is a disproportionate burden of cardiometabolic disease among African Americans (AA), though the environmental and/or genetic underpinnings remain incompletely defined. Because metabolites are downstream of genetic variation and transcriptional changes - and also integrate environmental factors - they serve as proximal reporters of human phenotypes. In prior work, we have identified and validated metabolite profiles of those destined to develop type 2 diabetes (T2D), including specific lipid and amino acid species, as well as their degradation products. However, existing studies have focused on relatively few metabolite classes and have not assessed metabolic dysregulation that presages diabetes in AA. To address important gaps in our scientific knowledge, this new proposal extends our investigations to AA in the Jackson Heart Study (JHS) and the Southern Community Cohort Study (SCCS). These studies also integrate novel metabolite profiling techniques developed by our group that markedly expand the breadth of analyses that can be measured. We will test the overarching hypothesis that metabolite profiling in well-phenotyped populations will illuminate T2D- associated metabolic pathways apart from those already described. In Specific Aim 1, we will identify new metabolomics biomarkers of insulin resistance and subclinical disease in the JHS and SCCS in cross-sectional analyses. In Specific Aim 2, we will examine whether baseline plasma metabolite profiles predict incident T2D in the JHS and the SCCS. In Specific Aim 3, we will characterize the genetic determinants of metabolites associated with insulin resistance and incident T2D. We will also test whether genetic variants that determine metabolite levels are in turn associated with clinical traits. This proposal leverages a novel small molecule profiling platform and the extensive genetic and phenotypic resources of both cohorts, with up to a decade of follow up. Our multidisciplinary collaboration includes investigators at the MGH, JHS, Vanderbilt and the Broad Institute, who bring collective expertise in metabolite profiling, biomarkers, genetic and population epidemiology, bioinformatics, metabolic traits, and health disparities. Since all data will be made publicly available in real time, this project will also produce a unique scientific resource for the entire investigative community.